A subject of the present invention is new derivatives of 2-aminopyridines which have an inhibitory activity on NO-synthase enzymes producing nitrogen monoxide NO and/or an activity which traps the reactive oxygen species (ROS). The invention relates to the derivatives corresponding to general formula (I) defined below, their preparation methods, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular their use as NO-synthase inhibitors and selective or non selective traps for reactive oxygen species.
Given the potential role of NO and the ROS""s in physiopathology, the new derivatives described corresponding to general formula (I) may produce beneficial or favourable effects in the treatment of pathologies where these chemical species are involved. In particular:
in the treatment of cardiovascular and cerebro-vascular disorders including for example atherosclerosis, migraine, arterial hypertension, septic shock, ischemic or hemorragic cardiac or cerebral infarctions, ischemias and thromboses.
in the treatment of disorders of the central or peripheral nervous system such as for example neurodegenerative diseases where there can in particular be mentioned cerebral infarctions, sub-arachnoid haemorrhaging, ageing, senile dementias including Alzheimer""s disease, Huntington""s chorea, Parkinson""s disease, Creutzfeld Jacob disease and prion diseases, amyotrophic lateral sclerosis but also pain, cerebral and bone marrow traumas, addiction to opiates, alcohol and addictive substances, erective and reproductive disorders, cognitive disorders, encephalopathies, encephalopathies of viral or toxic origin.
in the treatment of disorders of the skeletal muscle and neuromuscular joints (myopathy, myosis) as well as cutaneous diseases.
in the treatment of proliferative and inflammatory diseases such as for example atherosclerosis, pulmonary hypertension, respiratory distress, glomerulonephritis, portal hypertension, psoriasis, arthrosis and rheumatoid arthritis, fibroses, amyloidoses, inflammations of the gastro-intestinal system (colitis, Crohn""s disease) or of the pulmonary system and airways (asthma, sinusitis, rhinitis).
in treatments related to organ transplants.
in the treatment of auto-immune and viral diseases such as for example lupus, AIDS, parasitic and viral infections, diabetes, multiple sclerosis.
in the treatment of cancer.
in the treatment of neurological diseases associated with intoxications (Cadmium poisoning, inhalation of n-hexane, pesticides, herbicides), associated with treatments (radiotherapy) or disorders of genetic origin (Wilson""s disease).
in the treatment of all the pathologies characterized by an excessive production or dysfunction of NO and/or ROS""s.
In all these pathologies, there is experimental evidence demonstrating the involvement of NO or ROS""s (J. Med. Chem. (1995) 38, 4343-4362; Free Radic. Biol. Med. (1996) 20, 675-705; The Neuroscientist (1997) 3, 327-333).
Furthermore, NO Synthase inhibitors and their use have already been described by the inventors in previous Patents (U.S. Pat. No. 5,081,148; U.S. Pat. No. 5,360,925), as well as the combination of these inhibitors with products having antioxidant or antiradicular properties (Patent Application WO 98/09653). More recently, derivatives of amidines having NO Synthase inhibitory properties and/or antioxidant or antiradicular properties have been described in the Patent Applications WO 98/42696 and WO 98/58934.
The Applicant has now discovered a new class of compounds having an inhibitory activity on NO-synthases and/or an activity which traps the reactive oxygen species (ROS). These compounds, of general formula (I) defined hereafter, are derivatives of 2-aminopyridines.
The compounds according to the invention correspond to general formula (I) 
in which A represents a radical which traps free radicals, and in particular:
a radical 
in which R1, R2 and R3 represent, independently, a hydrogen atom, a halogen, the OH or SH group, a linear or branched alkyl, aralkoxy or alkoxy radical having from 1 to 6 carbon atoms, an xe2x80x94Oxe2x80x94COxe2x80x94R4, xe2x80x94SR4, xe2x80x94S(O)R4, xe2x80x94SO2R4, or xe2x80x94NR5R6 radical, or also R1 and R2 or R2 and R3 together form a methylenedioxy ring,
R4 representing a linear or branched alkyl radical having from 1 to 6 carbon atoms, and R5 and R6 representing independently a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or an aromatic ring optionally substituted by one or more groups chosen from a halogen atom, the OH group and a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms,
or NR5R6 constitutes a heterocycle with 4 to 6 members, which contains from 1 to 2 heteroatoms chosen from O, S and N, the corresponding members being respectively xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94NR7xe2x80x94,
R7 representing a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms,
or a radical 
in which Rxe2x80x21, Rxe2x80x22, Rxe2x80x23 and Rxe2x80x24 represent, independently, a hydrogen atom, a halogen, the OH group, or a linear or branched alkoxy radical having from 1 to 6 carbon atoms,
or also a radical 
in which R8 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms, a xe2x80x94COxe2x80x94R9 radical, an arylalkyl radical optionally substituted by one or more linear or branched alkyl or alkoxy radicals having from 1 to 6 carbon atoms,
R9 represents a linear or branched alkyl radical having from 1 to 6 carbon atoms;
X represents a xe2x80x94(CH2)m, xe2x80x94Qxe2x80x94, xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CHxe2x80x94Qxe2x80x94, xe2x80x94(CH2)mxe2x80x94C(xe2x95x90W)xe2x80x94Qxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR11xe2x80x94C(xe2x95x90W)xe2x80x94Qxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR11xe2x80x94C(xe2x95x90W)xe2x80x94Oxe2x80x94Qxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR11xe2x80x94C(xe2x95x90W)xe2x80x94NR12xe2x80x94Qxe2x80x94, xe2x80x94(CH2)mxe2x80x94NHxe2x80x94Zxe2x80x94NHxe2x80x94C(xe2x95x90W)xe2x80x94, xe2x80x94(CH2)mxe2x80x94Nxe2x95x90C(R16)xe2x80x94NR12xe2x80x94, xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CHxe2x80x94C(xe2x95x90W)xe2x80x94Q radical or a linear or branched alkenyl radical having from 1 to 6 carbon atoms,
Q representing a bond or a radical chosen from the piperazine, homopiperazine, piperidine, pyrrolidine or azetidine radicals, these radicals can be substituted by one or more linear or branched alkyl radicals having from 1 to 6 carbon atoms,
W representing one of the O or S atoms or the NH group,
Z representing a phenylene radical optionally substituted by one or more halogen atoms,
m being an integer comprised between 0 and 6;
Y represents an alkyl, alkenyl or alkynyl chain, each of these chains can be linear or branched, having up to 10 carbon atoms and be optionally substituted by an NR13, R14 radical, or Y represents a xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)pxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)pxe2x80x94 or xe2x80x94(CH2)nxe2x80x94NR13xe2x80x94(CH2)pxe2x80x94radical,
n and p being integers comprised between 0 and 6;
R10represents a hydrogen atom, one of the OH, CN, NO2 or xe2x80x94SR15 radicals, or a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms;
R11, R12, R13, R14 and R15 represent independently a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms;
R16 represents independently a hydrogen atom or a linear or branched alkyl or thioalkyl radical having from 1 to 6 carbon atoms;
It being understood that xe2x80x94Xxe2x80x94Yxe2x80x94 together do not represent a single bond, a linear or branched alkylene radical or an xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94NHxe2x80x94COxe2x80x94NH-alkylene radical;
it being also understood that when A represents the phenyl radical, xe2x80x94Xxe2x80x94Yxe2x80x94 together do not represent xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94;
or a salt of a product of general formula (I).
The compounds of the invention can exist in the state of bases or of addition salts in particular with organic or inorganic acids or with bases, and in particular in the state of hydrates.
By linear or branched alkyl having from 1 to 6 carbon atoms, is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. By linear or branched thioalkyl radicals having from 1 to 6 carbon atoms or linear or branched alkoxy having from 1 to 6 carbon atoms, are meant the thioalkyl or alkoxy radicals, the alkyl radical of which has the meaning indicated previously.
The term aryl refers to a hydrocarbon mono-, di ou tricyclic compound with at least one aromatic ring, each ring containing up to 7 members, such as for example phenyl, naphthyl, anthracyl, biphenyl or indenyl. The aryl radical is optionally substituted by one or more radicals chosen from the group constituted by a halogen atom, an alkyl radical, an alkoxy radical and a nitro radical. The term aralkoxy refers to an alkoxy radical substituted by an aryl radical as defined above.
Preferably, the compounds of general formula (I) as described above will be such that X represents one of the xe2x80x94NHxe2x80x94COxe2x80x94 or xe2x80x94COxe2x80x94Qxe2x80x94 radicals, Q representing one of the piperazine or homopiperazine radicals, these radicals can be substituted by one or more linear or branched alkyl radicals having from 1 to 6 carbon atoms. Furthermore, Y will preferably be chosen as being a xe2x80x94(CH2)nxe2x80x94NR13 xe2x80x94(CH2)pxe2x80x94 radical in which R13, n and p have the meanings indicated previously.
More preferentially, the compounds of general formula (I) described previously will be chosen such that:
A represents:
a radical 
in which R1, R2 and R3 represent, independently, a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms or an xe2x80x94NR5R6 radical, or also R1, and R2 or R2 and R3 together form a methylenedioxy ring,
R5 and R6 representing independently a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms, and preferably a hydrogen atom or a methyl or ethyl radical,
a 3,5-ditert-butyl-4-hydroxyphenyl or 4-(dimethylamino)phenyl radical,
or a radical 
in which Rxe2x80x21, Rxe2x80x22, Rxe2x80x23 and Rxe2x80x24 represent, independently, a hydrogen atom, the OH group, or a linear or branched alkoxy radical having from 1 to 6 carbon atoms, one at least of R1, R2, R3 and R4 preferably representing the OH group,
or also a radical 
in which R8 represents a hydrogen atom;
X represents one of the xe2x80x94NHxe2x80x94COxe2x80x94 or xe2x80x94COxe2x80x94Qxe2x80x94 radicals, Q representing a piperazine radical optionally substituted by one or two methyl radicals;
Y represents a xe2x80x94(CH2)nxe2x80x94NR13xe2x80x94(CH2)pxe2x80x94 radical in which R13 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms and n and p are integers comprised between 0 and 6, or Y represents an alkyl, alkenyl or alkynyl chain, each of these chains can be linear or branched and have up to 10 carbon atoms;
and R10represents a hydrogen atom or a methyl radical.
Quite particularly the following compounds of general formula (I) described in the examples will be preferred:
6-amino-N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-4-methyl-2-pyridine-pentanamide hydrochloride;
6-amino-N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-4-methyl-2-pyridine-butanamide hydrochloride;
6-amino-N-[4-(dimethylamino)phenyl]-4-methyl-2-pyridinebutanamide hydrochloride;
1-[4-(2-amino-5-pyridinyl)-3-butynyl]-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-piperazine hydrochloride;
1-[4-(2-amino-5-pyridinyl)butyl]-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-piperazine hydrochloride;
1-[2-(6-amino-4-methyl-2-pyridinyl)ethyl]-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-piperazine hydrochloride;
1-[4-(2-amino-6-pyridinyl)-3-butynyl]-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-piperazine hydrochloride;
N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2-hydroxy-5-methoxybenzamide hydrochloride;
N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2,6-dihydroxy-benzamide;
N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2,5-dihydroxybenzamide hydrochloride;
5-amino-N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2-hydroxybenzamide hydrochloride;
N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2,5-dihydroxy-3-methylbenzamide hydrochloride;
N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2,5-dihydroxy-3-(1-methylethyl)benzamide;
N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2-hydroxy-4,6-dimethoxy-benzamide hydrochloride;
N-[(6-amino-4-methyl-2-pyridinyl)butyl]-3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzamide hydrochloride;
6-amino-N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-methyl-2-pyridineheptanamide hydrochloride;
6-amino-N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-methyl-2-pyridinehexanamide hydrochloride;
6-amino-N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-methyl-2-pyridineacetamide hydrochloride;
xcex1-amino-N-[4-(dimethylamino)phenyl]-5-(6-amino-2-pyridinyl)-4-pentynamide hydrochloride;
xcex1,6-diamino-N-[4-(dimethylamino)phenyl]-2-pyridinyl-pentanamide hydrochloride;
6-amino-N-[4-(dimethylamino)phenyl]-4-methyl-2-pyridinehexanamide hydrochloride;
6-amino-N-[4-(dimethylamino)phenyl]-4-methyl-2-pyridineheptanamide hydrochloride;
N-[(6-amino-4-methyl-2-pyridinyl)butyl]-1,3-benzodioxole-5-carboxamide hydrochloride;
6-amino-N-[4-(dimethylamino)phenyl]-4-methyl-2-pyridinepentananamide hydrochloride;
{[4-(6-amino-4-methyl-2-pyridinyl)butyl]amino}-N-[(4-dimethylamino)phenyl]-acetamide hydrochloride;
6-amino-N-[3-(4-hydroxy-3-methoxy-phenyl)-2-propenyl]-4-methyl-2-pyridinebutanamine hydrochloride;
6-amino-N-[4-chloro-2-(phenylamino)phenyl]-4-methyl-2-pyridinepentanamide hydrochloride;
N-[(6-amino-4-methyl-2-pyridinyl)butyl]-1,3-benzodioxole-5-acetamide hydrochloride;
N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-N-(1,3-benzodioxole-5-ylmethyl)amine fumarate;
N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-N-[(E)-3-phenyl-2-propenyl]amine fumarate;
(E)-N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-3-(1,3-benzodioxole-5-yl)-2-propenamide fumarate;
2-({[4-(6-amino-4-methyl-2-pyridinyl)butyl]amino}methyl)-4-methoxyphenol;
N-[2-(benzyloxy)-4,5-dimethoxybenzyl]-4-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methyl-2-pyridinyl]-1-butanamine;
6-(4-{[2-(benzyloxy)-4,5-dimethoxybenzyl]amino}butyl)-4-methyl-2-pyridinamine;
2-({[4-(6-amino-4-methyl-2-pyridinyl)butyl]amino}methyl)-4,5-dimethoxyphenol;
N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-6-hydroxy-2,5,7,8-tetramethyl-2-chromanecarboxamide fumarate.
More preferably, the products of general formula (I) will be chosen from the group constituted by the following compounds:
6-amino-N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-4-methyl-2-pyridinepentanamide hydrochloride;
6-amino-N-[4-(dimethylamino)phenyl]-4-methyl-2-pyridinebutanamide hydrochloride;
1-[2-(6-amino-4-methyl-2-pyridinyl)ethyl]-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-piperazine hydrochloride;
N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2-hydroxy-5-methoxy-benzamide hydrochloride;
N-[(6-amino-4-methyl-2-pyridinyl)butyl-2,5-dihydroxy-benzamide hydrochloride;
N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2,5-dihydroxy-3-methyl-benzamide hydrochloride;
N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2,5-dihydroxy-3-(1-methylethyl)benzamide;
6-amino-N-[4-(dimethylamino)phenyl]-4-methyl-2-pyridinehexanamide hydrochloride;
N-[(6-amino-4-methyl-2-pyridinyl)butyl]-1,3-benzodioxole-5-carboxamide hydrochloride;
6-amino-N-[4-(dimethylamino)phenyl]-4-methyl-2-pyridinepentananamide hydrochloride;
{[4-(6-amino-4-methyl-2-pyridinyl)butyl]amino}-N-[(4-dimethylamino)phenyl]-acetamide hydrochloride;
6-amino-N-[3-(4-hydroxy-3-methoxy-phenyl)-2-propenyl]-4-methyl-2-pyridine-butanamine hydrochloride;
N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-N-(1,3-benzodioxole-5-ylmethyl)amine fumarate;
N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-N-[(E)-3-phenyl-2-propenyl]amine fumarate;
(E)-N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-3-(1,3-benzodioxole-5-yl)-2-propenamide fumarate;
2-({[4-(6-amino-4-methyl-2-pyridinyl)butyl]amino}methyl)-4-methoxyphenol;
6-(4-{[2-(benzyloxy)-4,5-dimethoxybenzyl]amino}butyl)-4-methyl-2-pyridinamine;
2-({[4-(6-amino-4-methyl-2-pyridinyl)butyl]amino}methyl)-4,5-dimethoxyphenol;
N-[4-(6-amino-4-methyl-2-pyridinyl)butyl]-6-hydroxy-2,5,7,8-tetramethyl-2-chromanecarboxamide fumarate.
Yet more preferably, the products of general formula (I) will be chosen from the group constituted by the following compounds:
6-amino-N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-4-methyl-2-pyridinepentanamide hydrochloride;
N-[(6-amino-4-methyl-2-pyridinyl)butyl]-2,5-dihydroxy-3-(1-methylethyl)benzamide;
6-amino-N-[4-(dimethylamino)phenyl]-4-methyl-2-pyridinepentananamide hydrochloride;
{[4-(6-amino-4-methyl-2-pyridinyl)butyl]amino}-N-[(4-dimethylamino)phenyl]acetamide hydrochloride;
6-amino-N-[3-(4-hydroxy-3-methoxy-phenyl)-2-propenyl]-4-methyl-2-pyridine-butanamine hydrochloride;
2-({[4-(6-amino-4-methyl-2-pyridinyl)butyl]amino}methyl)-4,5-dimethoxyphenol.
Moreover, the invention offers, as new industrial products, the compounds of general formula (II) and (III) 
in which A represents a radical which traps free radicals, and in particular:
a radical 
in which R1, R2 and R3 represent, independently, a hydrogen atom, a halogen, the OH or SH group, a linear or branched alkyl, aralkoxy or alkoxy radical having from 1 to 6 carbon atoms, an xe2x80x94Oxe2x80x94COxe2x80x94R4, xe2x80x94SR4, xe2x80x94S(O)R4, xe2x80x94SO2R4, or xe2x80x94NR5R6 radical, or also R1 and R2 or R2 and R3 together form a methylenedioxy ring,
R4 representing a linear or branched alkyl radical having from 1 to 6 carbon atoms, and R5 and R6 representing independently a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or an aromatic ring optionally substituted by one or more groups chosen from a halogen atom, the OH group and a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms,
or NR5R6 constitutes a heterocycle with 4 to 6 members, which contains from 1 to 2 heteroatoms chosen from O, S and N, the corresponding members being respectively xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94NR7xe2x80x94,
R7 representing a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms
or a radical 
in which Rxe2x80x21, Rxe2x80x22, Rxe2x80x23 and Rxe2x80x24 represent, independently, a hydrogen atom, a halogen, the OH group, or a linear or branched alkoxy radical having from 1 to 6 carbon atoms,
or also a radical 
in which R8 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms, a xe2x80x94COxe2x80x94R9 radical, an arylalkyl radical optionally substituted by one or more linear or branched alkyl or alkoxy radicals having from 1 to 6 carbon atoms,
R9 represents a linear or branched alkyl radical having from 1 to 6 carbon atoms;
X represents a xe2x80x94(CH2)mxe2x80x94Qxe2x80x94, xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CHxe2x80x94Qxe2x80x94, xe2x80x94(CH2)mxe2x80x94C(xe2x95x90W)xe2x80x94Qxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR11xe2x80x94C(xe2x95x90W)xe2x80x94Qxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR11xe2x80x94C(xe2x95x90W)xe2x80x94Oxe2x80x94Qxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR11xe2x80x94C(xe2x95x90W)xe2x80x94NR12xe2x80x94Qxe2x80x94, xe2x80x94(CH2)mxe2x80x94NHxe2x80x94Zxe2x80x94NHxe2x80x94C(xe2x95x90W)xe2x80x94, xe2x80x94(CH2)mxe2x80x94Nxe2x95x90C(R16)xe2x80x94NR12xe2x80x94xe2x80x94(CH2)mxe2x80x94CHxe2x95x90CHxe2x80x94C(xe2x95x90W)xe2x80x94Q radical or a linear or branched alkenyl radical having from 1 to 6 carbon atoms,
Q representing a bond or a radical chosen from the piperazine, homopiperazine, piperidine, pyrrolidine or azetidine radicals, these radicals can be substituted by one or more linear or branched alkyl radicals having from 1 to 6 carbon atoms,
W representing one of the O or S atoms or the NH group,
Z representing a phenylene radical optionally substituted by one or more halogen atoms,
m being an integer comprised between 0 and 6;
Y represents an alkyl, alkenyl or alkynyl chain, each of these chains can be linear or branched, having up to 10 carbon atoms and being optionally substituted by an NR13R14 radical, or Y represents a xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)pxe2x80x94, xe2x80x94(CH2nxe2x80x94Sxe2x80x94(CH2)pxe2x80x94 or xe2x80x94(CH2)nxe2x80x94NR13xe2x80x94(CH 2)pxe2x80x94 radical,
n and p being integers comprised between 0 and 6;
R10represents a hydrogen atom, one of the OH, CN, NO2 or xe2x80x94SR15 radicals, or a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms;
R11, R12, R13, R14 and R15 represent independently a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms;
R16 represents independently a hydrogen atom or a linear or branched alkyl or thioalkyl radical having from 1 to 6 carbon atoms;
and Yxe2x80x2 represents a a linear or branched alkyl chain having from 1 to 8 carbon atoms;
It being understood that xe2x80x94Xxe2x80x94Yxe2x80x94 together do not represent a single bond, a linear or branched alkylene radical or an xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94NHxe2x80x94COxe2x80x94NH-alkylene radical;
it being also understood that when A represents the phenyl radical, xe2x80x94Xxe2x80x94Yxe2x80x94 together do not represent xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94;
it being finally understood that, for the compound of general formula (III) only, when A represents the phenyl radical, a phenyl radical substituted by one or more halogen atoms or the: naphthyl radical, X does not represent xe2x80x94NHxe2x80x94COxe2x80x94 or xe2x80x94COxe2x80x94Qxe2x80x2xe2x80x94 in which Qxe2x80x2 is the piperazine radical.
In certain cases, the compounds according to the present invention (i.e. in particular the compounds of general formulae (I), (II) and (III) described previously) can contain asymmetrical carbon atoms, and therefore have two possible enantiomeric forms, i.e. xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d configurations The present invention includes the two enantiomeric forms and all combinations of these forms, including xe2x80x9cRSxe2x80x9d racemic mixtures. In an effort to simplify matters, when no specific configuration is indicated in the structural formulae, it should be understood that the two enantiomeric forms and their mixtures are represented.
A subject of the invention is also, as medicaments, the compounds of general formula (I) described previously or their pharmaceutically acceptable salts. It also relates to pharmaceutical compositions containing these compounds or their pharmaceutically acceptable salts, and the use of these compounds or of their pharmaceutically acceptable salts for producing medicaments intended to inhibit neuronal NO synthase or inducible NO synthase, to inhibit lipidic peroxidation or to provide the double function of NO synthase inhibition and lipidic peroxidation inhibition.
By pharmaceutically acceptable salt is meant in particular addition salts of inorganic acids such as hydrochloride, sulphate, phosphate, diphosphate, hydrobromide and nitrate, or of organic acids, such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methane sulphonate, p-toluenesulphonate, pamoate, oxalate and stearate. The salts formed: from bases such as sodium or potassium hydroxide also fall within the scope of the present invention, when they can be used. For other examples of pharmaceutically acceptable salts, reference can be made to xe2x80x9cPharmaceutical saltsxe2x80x9d, J. Pharm. Sci. 66:1(1977).
The pharmaceutical composition can be in the form of a solid, for example powders, granules, tablets, gelatin capsules, liposomes or suppositories. Appropriate solid supports can be for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
The pharmaceutical compositions containing a compound of the invention can also be presented in the form of a liquid, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.
A medicament according to the invention can be administered by topical, oral or parenteral route, by intramuscular injection, etc.
The envisaged administration dose for the medicament according to the invention is comprised between 0.1 mg and 10 g according to the type of active compound used.
In accordance with the invention, the compounds of general formula (I) can be prepared by the process described below.
The compounds of general formula (I), in which A, X, Y and R10 are as defined above, can be prepared from the intermediates of general formula (II) or the intermediates of general formula (III) and (IV) according to diagram 1. 
The final molecules of general formula (I) are obtained after detachment of the protective group 2,5-dimethyl pyrrole from the compounds of general formula (II) by heating in the presence of hydroxylamine hydrochloride, at a temperature which varies from 60xc2x0 C. to 100xc2x0 C., in a solvent such as for example ethanol according to an experimental protocol described in J. Chem. Soc. Perkin Trans. (1984), 2801-2807.
When the compounds of general formula (I) carry an amine protected by a labile group in acid medium (for example: tert-butyl carbamatem, this is released during the final salification stage carried out, in this case, using a strong acid, in particular HCl.
Alternatively the compounds of general formula (I) can be obtained by heating alkynes of general formula (III) with the halogeno-pyridine intermediates of general formula (IV), either in the presence of Palladium(0) derivatives, such as Pd(PPh3)4 operating under an inert atmosphere in n-butylamine, or in the presence of a Palladium (II) derivative, such as Pd(OAc)2, and PPh3 in piperidine (J. Med. Chem., (1996), 36 (16), 3179-3187). The acetylenic derivatives of general formula (I) thus obtained can be optionally converted into ethylenic derivatives by reduction either under a hydrogen atmosphere in the presence of a catalyst of Lindlar type or by reduction in the presence of a hydride such as RedA1 (J. Org. Chem., (1988), 53, 3845). The acetylenic compounds of general formula (I) can also be reduced by Pd/C under a hydrogen atmosphere in an alcoholic solvent such as ethanol in order to directly lead to the corresponding alkanes.
When the compounds of general formula (III) carry a protected amine (principally in the form of tert-butyl carbamate), this is released after condensation (III)+(IV) during the final salification stage of the molecules in the presence of a strong acid (for example HCl).
A) The Compounds of General Formula (II) Can be Prepared According to the Following Methods:
The synthetic precursors which lead to the intermediates of general formula (II) are prepared from compounds of general formula (II.1), such as for example 2-(2,5-dimethylpyrrol-1-yl)-4,6-dimethylpyridine. This is obtained from commercial 6-amino-2,4-lutidine according to an experimental protocol described in J. Chem. Soc. Perkin Trans., (1984), 12, 2801-2807. Treatment of the compounds of general formula (II.1) by a strong base such as, for example, nBuLi, at a temperature which varies from xe2x88x9250xc2x0 C. to xe2x88x9230xc2x0 C. in an anhydrous solvent such as ethyl ether, under an inert atmosphere and optionally in the presence of N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine allows the formation of the lithiated derivative (intermediate (II.2)) which in the presence of an electrophile E+ leads to the adducts of general formula (II.X). 
Among the electrophiles E+ which can react on the lithiated type of general formula (II.2), there can be mentioned for example CO2, halogeno-esters, halogeno-orthoesters, paraformaldehyde, protected halogeno-alcohols (for example in the form of tetrahydropyrane acetal) or protected halogeno-amines.
1.1) Preparation of Alcohols of General Formula (II.3):
The action of the derivative (II.2) on paraformaldehyde or on protected halogeno-alcohols allows access, after optional deprotection, to the alcohols of general formula (II.3), in which Y and R10 are as defined above. 
1.2) Preparation of Aldehydes of General Formula (II.4)
The aldehydes of general formula (II.4), in which Y and R10 are as defined above, can be prepared by oxidation of the alcohols of general formula (II.3) and by using, for example oxalyl chloride in DMSO (Swern oxidation) or a pyridine-sulphurtrioxide complex in the presence of a base such as triethylamine (Tetrahedron Lett., (1982), 23, 807): 
Or these aldehydes are also accessible by the condensation of the intermediates of general formula (II.2) with the derivatives of halogeno-acetal type followed by a standard deprotection stage in an acid medium: 
1.3) Preparation of Carboxylic Acids of General Formula (II.6):
The action of the intermediate (1I.2) on CO2 and on the halogeno-ester or orthoester derivatives allows access, after optional deprotection, to the carboxylic acids of general formula (II.6), in which Y and R10 are as defined above: 
These acids can also be obtained by the oxidation of aldehydes of general formula (II.4) by silver nitrate according to an experimental protocol described in J. Org. Chem., (1985), 50, 2981-2987.
1.4) Preparation of Amines of General Formula (II.7):
The alcohols of general formula (II.3), described previously, allow access to amines of general formula (II.7) in which Q, Y and R10, are as defined above. The alcohol function is activated fin a standard fashion in the form of a sulphonate derivative of general formula (II.8) before being displaced by an amine and in particular a heterocyclic amine. Condensation is carried out in the presence of Caesium carbonate and LiI at a temperature of 70xc2x0 C. to 100xc2x0 C. and in particular under reflux of butanone. The heterocycles such as piperazine are used in mono-protected form (e.g. Boc) during the condensation and an additional selective deprotection is then necessary in order to release the second amine function: 
In the particular case where Q is a single bond and Y=xe2x80x94HN(R13)xe2x80x94(CH2)pxe2x80x94, the amines of general formula (II.7) are prepared from intermediate (II.2) which is condensed on protected halogeno-amines (for example in the form of silylated or phthalimide derivatives) under the conditions described previously. The primary amines of general formula (II.7) are finally obtained after deprotection under the conditions described in the literature (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)). 
2.1) Carboxamides of General Formula (II):
2.1.1) The carboxamides of general formula (II), in which A, X, Y and R10 are as defined above, are prepared by condensation of the amines of general formula (A.1) with the acids of general formula (II.6), described previously, according to the standard methods used in peptide condensation (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis (Springer-Verlag, 1984)). The synthesis of the non-commercial amines of general formula (A.1), is described further on. 
2.1.2) The carboxamides of general formula (II), in which A, X, Y and R10 are as defined above, can also be prepared by condensation of the carboxylic acids of general formula (A.2) with the amines of general formula (II.7) under the conditions described previously. The synthesis of the non commercial carboxylic acids of general formula (A.2), is described further on. 
2.2) Amines of General Formula (II):
2.2.1) The amines of general formula (II), in which A, X, Y and R10 are as defined above, are prepared by condensation of an amine of general formula (A.1) or (A.3) with an aldehyde of general formula (II.4) during a reducing amination stage in the presence of a reducing agent, such as for example sodium borohydride or sodium triacetoxyborohydride and in a solvent such as, for example, 1,2-dichloroethane. The synthesis of the amines of general formula (A.3) is described further on. 
2.2.2) The amines of general formula (II), in which A, X, Y and R10 are as defined above, can also be prepared by condensation of the aldehydes of general formula (A.4) or the cinnamaldehyde derivatives of general formula (A.5) with the amines of general formula (II.7) under the conditions described previously: 
3.1) Synthesis of the Amines of General Formula (A.1):
In the particular case where A is a phenolic derivative, the anilines of general formula (A.1) are obtained by hydrogenation, in the presence of a catalytic quantity of Pd/C, of the corresponding nitrophenol derivatives, themselves synthesized according to a method described in the literature (J. Org. Chem., (1968), 33 (1), 223-226). The amino-diphenylamines of general formula (A.1) are accessible from methods described in the literature (Synthesis (1990) 430; Indian J. Chem. (1981) 20B, 611-613; J. Med. Chem. (1975) 18(4), 386-391). The nitro-diphenylamines obtained in an intermediate fashion lead, either by catalytic hydrogenation, or by using SnCl2 (J. Heterocyclic Chem. (1987), 24, 927-930; Tetrahedron Letters (1984), 25, (8), 839-842) to the amino-diphenylamines of general formula (A.1).
3.2) Synthesis of the Carboxylic Acids of General Formula (A.2):
The carboxylic acids of general formula (A.2) can be prepared according to the methods described in the literature: Can. J. Chem. (1972), 50, 1276-1282, J. Org. Chem. (1961) 26, 1221-1223 or Acta Chem. Scandinavica (1973) 27, 888-890.
3.3) Synthesis of the Amines of General Formula (A.3):
The amines of general formula (A.3), in which A, X and n are as described previously, are prepared, in two stages, by condensation of the amines of general formula (A.1) with the commercial protected amino acids, of general formula (A.6) under standard conditions of peptide synthesis described previously. Deprotection of the terminal amine of the intermediate of general formula (A.7) is then carried out during the last stage, and for example in a strong acid medium in order to detach the tert-butoxycarbonyl function: 
B) The Compounds of General Formula (III) can be prepared according to the following methods:
The acetylenic compounds of general formula (III), in which A, Q, W, Y and m are as defined above, are prepared by nucleophilic substitution of the commercial acetylenic derivatives of general formula (B.1), in which Gp is a labile group such as halogen or sulphonic derivatives, by an amine of general formula (B.2) according to a procedure described in J. Med. Chem., (1996), 39 (16), 3179-3187. 
The amines of general formula (B.2) are easily accessible from methods described in the literature (e.g.: J. Med. Chem., (1992), 35 (23), 4464-4472).
C) The Compounds of General Formula (IV) Can be Prepared According to the Following Methods:
The non-commercial halogenated derivatives of 2-aminopyridine of general formula (IV), in which R10 is as defined above, can be prepared according to methods described in the literature and in particular those described in J. Org. Chem., (1962), 27, 2473-2478, Rec Trav. Chim., (1966), 85, 803 or Aust. J. Chem., (1982), 25, 2025-2034.
Unless they are defined differently, all the technical and scientific terms used here have the same meaning as that usually understood by an ordinary specialist in the field to which the invention belongs. Similarly, all publications, patent applications, patents and other references mentioned here are incorporated by way of reference.